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Abstract:

The invention provides a patch preparation containing (a) a support and
(b) an adhesive layer containing a drug on the surface of the support,
wherein a crystal of the drug is formed in the adhesive layer immediately
after application of a physical stimulation to the adhesive layer, while
a crystal of the drug is formed during preservation after the physical
stimulation. The patch preparation which does not require an increase in
the area and thickness of an adhesive layer, achieves a sufficiently high
skin permeation amount of the drug, shows good adhesiveness to skin, and
permits a long-term adhesion to skin. The invention also provides a
method of producing the patch preparation.

Claims:

1. A patch preparation comprising: a support; and an adhesive layer
containing a drug on one surface of the support, wherein a crystal of the
drug is not formed in the adhesive layer immediately after application of
a physical stimulation to the adhesive layer, while a crystal of the drug
is formed during preservation after the physical stimulation.

2. The patch preparation of claim 1, wherein the drug in the adhesive
layer is dissolved in the adhesive layer.

3. The patch preparation of claim 1, wherein a crystal of the drug is
formed not less than 24 hr and within 6 months when the patch preparation
is preserved at not more than 25.degree. C. after application of physical
stimulation.

4. A method of producing the patch preparation of claim 1, comprising a
step of heating the adhesive layer containing the drug to a temperature
less than the melting point of the drug.

5. The patch preparation of claim 2, wherein a crystal of the drug is
formed not less than 24 hr and within 6 months when the patch preparation
is preserved at not more than 25.degree. C. after application of physical
stimulation.

6. A method of producing the patch preparation claim 2, comprising a step
of heating the adhesive layer containing the drug to a temperature less
than the melting point of the drug.

7. A method of producing the patch preparation claim 3, comprising a step
of heating the adhesive layer containing the drug to a temperature less
than the melting point of the drug.

8. A method of producing the patch preparation claim 5, comprising a step
of heating the adhesive layer containing the drug to a temperature less
than the melting point of the drug.

Description:

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to a patch preparation comprising an
adhesive layer containing a drug on one surface of a support, and a
production method thereof.

BACKGROUND OF THE INVENTION

[0002] To increase the skin permeation amount of a drug during application
of a patch preparation to the skin, the amount of a drug in the patch
preparation may be increased. To increase the amount of a drug in an
adhesive layer, the area and thickness of the adhesive layer of a patch
preparation may be increased. However, such embodiment deteriorates the
handling property of the patch preparation. Since transfer of a drug into
the skin is known to depend on the concentration of the drug in an
adhesive layer of a patch preparation, the skin permeation amount of a
drug may be increased by increasing the drug concentration of the
adhesive layer.

[0003] On the contrary, a patch preparation with a higher drug
concentration tends to readily form a crystal of the drug. When the
amount of the crystal of the drug is small, it does not adversely
influence the usefulness of a patch preparation. However, even when the
amount of the crystal formation of the drug is small, inconveniences may
be induced such as patients' concern about the quality degradation,
thereby making them hesitate to use the preparation and the like. When
the amount of the crystal formation of the drug is high, not only the
drug release characteristic changes but also an adhesive area decreases
when the crystal covers the surface of the adhesive layer. As a result,
the adhesiveness to the skin may decrease and the patch preparation may
not be able to maintain the adhesiveness for a long time.

[0004] Therefore, a patch preparation capable of increasing a drug skin
permeation amount, reducing the area and thickness of an adhesive layer
of the patch preparation, thereby improving handling property and
compliance by decreasing irritation and uncomfortableness during adhesion
and the like, and maintaining the adhesiveness to the skin for a long
time is desired.

[0005] JP-B-3566301, National Publication of International Patent
Application No. 2006-513195, JP-B-2610314, JP-B-4166276, and National
Publication of International Patent Application No. 2001-514213 teach
that crystal formation of a drug can be suppressed by heating a laminated
sheet containing a drug-containing adhesive layer, or a patch preparation
precursor, or a laminated sheet and a patch preparation precursor. In all
these publications, however, since the heating temperature is not less
than the melting point of a drug, the drug is melted as well as exposed
to a high temperature, thus possibly resulting in denaturation of the
drug. Moreover, these publications are silent on the problems of crystal
formation of drug that may occur when a patch preparation is actually
applied to the skin, even when a crystal of the drug was not formed
during the production steps of the patch preparation.

SUMMARY OF THE INVENTION

[0006] It is therefore an object of the present invention to provide a
patch preparation which does not require increase in the area and
thickness of an adhesive layer, achieves sufficiently high skin
permeation amount of a drug (i.e., having superior drug release
characteristic), shows good adhesiveness to the skin and permits a
long-term adhesion, and a production method thereof.

[0007] In addition, the present invention aims to provide a patch
preparation which does not give rise to patients' concern about the
quality degradation during use, achieves sufficiently high skin
permeation amount of a drug (i.e., having superior drug release
characteristic), shows good adhesiveness to the skin and permits a
long-term adhesion, and a production method thereof.

[0008] To achieve the above-mentioned object, the present invention has
the following constitution.

[0009] Accordingly, the present invention relates to

[1] a patch preparation comprising: a support; and an adhesive layer
containing a drug on one surface of the support,

[0010] wherein a crystal of the drug is not formed in the adhesive layer
immediately after application of a physical stimulation to the adhesive
layer, while a crystal of the drug is formed during preservation after
the physical stimulation.

[2] the patch preparation of [1], wherein the drug in the adhesive layer
is dissolved in the adhesive layer, [3] the patch preparation of [1] or
[2], wherein a crystal of the drug is formed not less than 24 hr and
within 6 months when the patch preparation is preserved at not more than
25° C. after application of physical stimulation, [4] the patch
preparation of [1] or [2], wherein a crystal of the drug is formed not
less than 24 hr and within 6 months when the patch preparation is
preserved in an environment of 25° C.±5° C., relative
humidity 60% RH±5% RH after application of physical stimulation, and
[5] a method of producing the patch preparation of any one of the
above-mentioned [1]-[4], comprising a step of heating the adhesive layer
containing the drug to a temperature less than the melting point of the
drug.

[0011] In addition, the present invention relates to

[6] a method of producing a patch preparation comprising: a support; and
an adhesive layer containing a drug on the surface of the support, which
is provided on one surface of a support, comprising

[0012] a step of cutting a laminated sheet wherein support/adhesive layer
containing a drug/release liner are laminated in this order into the form
and size of a patch preparation to give a patch preparation precursor,
and a step of heating the patch preparation precursor at not less than
40° C. and less than 100° C. and less than the melting
point of the drug,

[7] the method of the above-mentioned [6], wherein the patch preparation
precursor is heated for 3-120 hr, and [8] the method of the
above-mentioned [6] or [7], wherein the concentration of the drug in the
adhesive layer is 100-300% to the saturating concentration of the drug in
the adhesive layer.

[0013] According to the present invention, a patch preparation which does
not require increased area and thickness of an adhesive layer, achieves
sufficiently high skin permeation amount of a drug, shows good
adhesiveness to the skin and permits a long-term adhesion, and a
production method thereof can be provided.

[0014] In addition, according to the present invention, patch preparation
which does not give rise to patients' concern about the quality
degradation during use, achieves sufficiently high skin permeation amount
of a drug (i.e., having superior drug release characteristic), shows good
adhesiveness to the skin and permits a long-term adhesion can be
obtained.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The patch preparation of the present invention comprises an
adhesive layer containing a drug, which is formed on one surface of a
support, and is characterized in that a crystal of the drug is not formed
in the adhesive layer immediately after application of a physical
stimulation to the adhesive layer of the patch preparation; while a
crystal of the drug is formed during preservation after the physical
stimulation.

[0016] When the crystal of the drug is formed in the adhesive layer from
immediately after physical stimulation of the adhesive layer, even if the
amount of the crystal of the drug is small and the crystal does not
adversely influence the usefulness of the patch preparation, patients may
have concern about the quality degradation and hesitate to use the
preparation. When the amount thereof is high, not only the drug release
characteristic changes but also the crystal covers the surface of the
adhesive layer and reduces the adhesive area. As a result, the
adhesiveness to the skin may decrease and the patch preparation may not
be able to maintain the adhesiveness for a long time.

[0017] In the present invention, "a crystal of the drug is not formed in
the adhesive layer immediately after application of a physical
stimulation to the adhesive layer" means a crystal of the drug is not
formed in the adhesive layer during preservation for not less than 0 hr
and less than 24 hr from the application of physical stimulation on the
adhesive layer.

[0018] Here, "a crystal of the drug is not formed in the adhesive layer"
basically means that a crystal of the drug is not found in the adhesive
layer by visual observation, and in a preferable embodiment, it means
that a crystal of the drug is not found in the adhesive layer both by
visual observation and microscopic observation (maximum magnification
×500). In addition, "physical stimulation" means that the adhesive
layer of a patch preparation is pierced through with a toughened and
sharp-pointed part of a tool, for example, the adhesive layer of a patch
preparation is pierced through with the edge of a cutter, the adhesive
layer is cut with the toughened and sharp-pointed part and the like.

[0019] In the patch preparation of the present invention, a crystal of the
drug is preferably formed during the preservation term of not less than
24 hr (=1 day) and within 6 months, more preferably not less than 1 week
(=7 days) and within 6 months, from the application of physical
stimulation on the adhesive layer.

[0020] When a crystal of the drug is formed less than 24 hr from the
application of physical stimulation on the adhesive layer (that is, a
crystal of the drug is formed immediately after application of physical
stimulation on the adhesive layer), the concentration of the drug in the
adhesive layer is too high. In this case, crystal formation of the drug
might have occurred when actually using the patch preparation, possibly
causing difficulty in use. As a result, patients may have concern about
the quality degradation during use and, when a crystal precipitates on
the surface of the adhesive layer, the area having adhesiveness decreases
and the adhesiveness to the skin may decrease.

[0021] On the other hand, when crystal formation of the drug requires
longer than 6 months from the application of physical stimulation, the
concentration of the drug in the adhesive layer is assumed to be low. In
this case, a sufficient skin permeation amount of the drug may be
difficult to achieve.

[0022] In the patch preparation of the present invention, a crystal of the
drug is not formed in the adhesive layer immediately after application of
a physical stimulation to the adhesive layer, while a crystal of the drug
is formed during preservation after the physical stimulation. The reason
therefor is assumed that the adhesive layer containing the drug at a
reasonably high concentration forms a crystal core of the drug when the
adhesive layer is subject to a physical stimulation; whereby the core of
the crystal of the drug gradually grows during preservation of the patch
preparation.

[0023] The "preservation" in the present specification means that a patch
preparation is stood under an environment of temperature 25°
C.±5° C. and relative humidity 60% RH±5% RH.

[0024] The patch preparation of the present invention is preferably free
of a crystal of a drug in an adhesive layer immediately after production.
When even a slight amount of a crystal of a drug is contained in the
adhesive layer, the crystal may grow during preservation even in the
absence of a particular physical stimulation on the patch preparation and
produce a large amount of the crystal of the drug. Therefore, the drug is
preferably dissolved in the adhesive layer immediately after production.

[0026] To sufficiently afford the effect of the present invention, the
drug is advantageously a solid drug at room temperature (25° C.).
The solid drug at room temperature means a drug having its melting point
higher than 25° C. as measured by DSC (differential scanning
calorimeter). The melting point here is an extrapolation melting start
temperature in a DSC curve measured according to JIS K 7121-1987 and
using DSC. The extrapolation melting start temperature is a temperature
at the intersection point between a straight line extending from the
baseline on the low temperature side toward the high temperature side,
and a tangent line to the curve on the low temperature side of the
meltpeak at the point of maximum gradient.

[0027] The drug of which crystallization peak in the measurement by DSC is
not detected is preferable. Using such a drug, formation of the drug
crystal in the adhesive layer immediately after production of a patch
preparation (before preservation of the patch preparation) can be
certainly suppressed. Since a drug of which crystallization peak is not
detected does not easily form its crystal structure, such a drug is
assumed to be less apt to form a crystal in the adhesive layer.

[0028] The crystallization peak means an exothermic peak due to
crystallization of a drug as measured according to JIS K 7121-1987 and
using DSC. To be specific, 5 mg-10 mg of a drug is measured in a
measurement container, and the peak is measured by the following
temperature program to give a DSC curve. The drug is maintained at a
temperature lower by 50° C. than the melting point of the drug for
10 min, heated at a temperature raise rate of 2° C. per minute,
and maintained at a temperature higher by 30° C. than the melting
point for 3 min. Thereafter, the temperature is decreased at a rate of
2° C. per minute, and the drug is maintained at a temperature
lower by 30° C. than the glass transition temperature of the drug
for 10 min, and then heated again at a rate of 2° C. per minute to
a temperature higher by 30° C. than the melting point of the drug.

[0029] The glass transition temperature is a middle point of step-like
changes accompanying the glass transition of the drug in the
above-mentioned DSC curve. The middle point of the step-like changes is a
temperature at an intersection point between a straight line located at
an equal distance from two straight lines, which are extended baselines
before and after the step-like changes, and the curve of the step-like
changing part of glass transition.

[0030] The aforementioned melting point is an extrapolation melting start
temperature of an endothermic peak accompanying drug melting in the
above-mentioned DSC curve.

[0031] Examples of the drug of which crystallization peak by DSC analysis
is not detected include donepezil, miconazole, diltiazem, scopolamine,
ketoprofen, indomethacin, capsaicin, ibuprofen, isosorbide dinitrate,
diclofenac, rotigotine and the like.

[0032] In one embodiment of the present invention, the drug is donepezil
and/or a pharmaceutically acceptable salt thereof. In another embodiment
of the present invention, the drug is a drug other than donepezil and/or
a pharmaceutically acceptable salt thereof.

[0033] The drug is present in the adhesive layer in an amount sufficient
to provide desired results in the treatment of disease, condition or
disorder, for example, desired therapeutic effect, (to be referred to as
an effective amount in the present specification). The effective amount
of the drug means, for example, an amount of the drug that provides a
concentration of the drug in blood lower than a toxic level and
sufficient to provide a selected effect over a predetermined time.

[0034] Such amount can be easily determined by those of ordinary skill in
the art.

[0035] The weight concentration of the drug in the adhesive layer is not
particularly limited as long as it is within the range of the
above-mentioned effective amount, can ensure sufficient skin permeation
amount of the drug, and does not impair adhesion property of the
adhesive. For example, the weight concentration is 0.1-60 wt %,
preferably 0.5-40 wt %, relative to the whole adhesive layer. When the
weight concentration is less than 0.1 wt %, the treatment effect may be
insufficient, and when it exceeds 60 wt %, the content of an adhesive
constituting the adhesive layer becomes small, and sufficient skin
adhesiveness may not be achieved, which is economically disadvantageous.

[0036] The weight concentration (wt %) of the drug in an adhesive layer is
a ratio of the weight concentration (wt %) to the saturating
concentration (wt %) of the drug in the adhesive layer, and is preferably
100-300%, more preferably 100-250%. When the ratio of the weight
concentration to the saturating concentration [(weight
concentration/saturating concentration)×100(%)] is less than 100%,
sufficiently high skin permeation amount of the drug tends to be
difficult to achieve, since the drug concentration of the adhesive layer
is low. When it exceeds 300%, crystal formation of the drug tends to
occur even if a physical stimulation is not applied to the adhesive layer
during the production step of the patch preparation or after production
thereof.

[0037] In addition, a saturating concentration of a drug in an adhesive
layer can be determined by the following operation. Patch preparations
with an adhesive layer having an incrementing drug concentration by 1 wt
% are prepared, a liner on the adhesive layer of the respective patch
preparations is detached, a small amount of a drug is left standing on
the exposure face of the respective adhesive layers, and the liner is
laminated again on the adhesive layer. The thus-produced patch
preparations are stored in an incubator at 25° C. for 6 months,
and the size change of the drug left on the adhesive layer is observed
every month under an optical microscope (magnification: 500-fold). When
the drug size increases, the drug concentration is judged to have
exceeded the saturating concentration, when the drug size decreases, the
drug concentration is judged to be less than the saturating
concentration, and when the drug size does not change, the drug
concentration is judged to be near the saturating concentration.

[0038] This measurement method is based on the following facts. When the
drug concentration is drastically smaller than the saturating
concentration, the drug stood dissolves in the adhesive layer to reduce
the drug size, when the drug concentration is higher than the saturating
concentration, crystal grows from the drug stood to increase the drug
size, and when the drug concentration is near the saturating
concentration, the drug size does not change since dissolution and growth
of the drug stood are equilibrated.

[0039] For example, when the size of the drug stood becomes small in a
patch preparation having a drug concentration of 1-5 wt %, does not
change in a patch preparation having a drug concentration of 6-7 wt %,
and increases in a patch preparation having a drug concentration of 8-10
wt %, the saturating concentration of the drug in an adhesive layer is 7%
(wt %). When the saturating concentration is judged to be less than 1%
according to this method (when the size of the drug stood increases in a
patch preparation having a drug concentration of 1 wt %), a patch
preparation having an incrementing drug concentration by 0.2 wt % within
the range of 0-1 wt % is prepared, and evaluated in the same manner as
above, and a saturating concentration is determined.

[0040] In the patch preparation of the present invention, the support is
not particularly limited, and various plastic films, non-woven fabric,
paper, woven fabric, knitted fabric, metal foil, and laminate of these
can be used. When desired, a metal may be applied thereon by vapor
deposition. The plastic film is not particularly limited, and various
films formed from a polyvinyl chloride single substance, or a copolymer
of a monomer such as ethylene, propylene, vinyl acetate, acrylic acid,
acrylic acid ester, methacrylic acid, methacrylic acid ester,
acrylonitrile, styrene, vinylidene chloride and the like, and other
monomer, or an olefin system polymer such as polyethylene, polypropylene,
ethylene-vinyl acetate copolymer and the like; a polyester system polymer
such as polyethylene terephthalate, polyetherpolyester and the like; a
polyamide system polymer such as polyetherpolyamide block polymer and the
like, and the like can be used. The thickness of the support is generally
10-500 μm, preferably 10-200 μm.

[0041] The adhesive layer is a layer-like structure containing a polymer
and shows adhesiveness at ambient temperature (25° C.). In view of
the handling property of the preparation, the thickness of the adhesive
layer is preferably 10-500 μm, more preferably 15-300 μm,
particularly preferably 20-250 μm.

[0042] The polymer to be contained in an adhesive layer is not
particularly limited, and examples thereof include acrylic polymers
comprising (meth)acrylic acid ester system polymer; rubber polymers such
as styrene-diene-styrene block copolymer (e.g., styrene-isoprene-styrene
block copolymer, styrene-butadiene-styrene block copolymer),
polyisoprene, polyisobutylene, polybutadiene and the like; silicone
polymers such as silicone rubber, dimethylsiloxane base, diphenylsiloxane
base and the like; vinyl ether polymers such as polyvinyl methylether,
polyvinyl ethylether, polyvinyl isobutylether and the like; vinyl ester
polymers such as vinyl acetate-ethylene copolymer and the like; polyester
polymers comprising an carboxylic acid component such as
dimethylterephthalate, dimethylisophthalate, dimethylphthalate and the
like and a polyvalent alcohol component such as ethylene glycol and the
like, and the like.

[0043] As an acrylic polymer, one containing alkyl (meth)acrylate as a
main component, and obtained by copolymerization with a functional
monomer, is preferable. That is, a copolymer containing 50-99 wt %
(preferably 60-95 wt %) of a monomer component comprised of alkyl
(meth)acrylate, and the remaining monomer component comprised of a
functional monomer is preferable. The main component here means a monomer
component contained in a proportion of not less than 50 wt % of the total
weight of the monomer component constituting the copolymer.

[0044] In alkyl (meth)acrylate (hereinafter to be also referred to as the
main component monomer), the alkyl group generally consists of a straight
chain or branched alkyl group having a carbon number of 4-13 (e.g.,
butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl,
dodecyl, tridecyl and the like), and one or more kinds thereof are used.

[0046] One or more kinds of the functional monomers can be used and, among
them, a carboxyl group-containing monomer is preferable, and
(meth)acrylic acid is particularly preferable, from the aspects of
pressure-sensitive adhesiveness of the adhesive layer, cohesiveness, the
release characteristic of the drug contained in the adhesive layer, and
the like.

[0047] As an acrylic polymer, a copolymer of the above-mentioned alkyl
(meth)acrylate (main monomer component) and a functional monomer, which
is further copolymerized with other monomer, can also be used.

[0048] Examples of other monomer include (meth)acrylonitrile, vinyl
acetate, vinyl propionate, N-vinyl-2-pyrrolidone, methylvinylpyrrolidone,
vinylpyridine, vinylpiperidone, vinylpyrimidine, vinylpiperazine,
vinylpyrrole, vinylimidazole, vinylcaprolactam, vinyloxazole and the
like, and one or more kinds thereof can be used.

[0049] The amount of other monomer to be used is generally preferably
about 0-40 wt %, more preferably about 10-30 wt %, relative to the total
weight of alkyl (meth)acrylate (main monomer component) and a functional
monomer.

[0050] As a specific preferable example of the acrylic polymer, a
terpolymer of 2-ethylhexyl acrylate as alkyl (meth)acrylate, acrylic acid
and N-vinyl-2-pyrrolidone is preferable, and a copolymer obtained by
copolymerization of 2-ethylhexylacrylate, acrylic acid and
N-vinyl-2-pyrrolidone at a weight ratio of 40-99.9:0.1-10:0-50 is more
preferable, since adhesiveness to the human skin is fine, and adhesion
and detachment can be repeated easily.

[0051] Of the rubber polymers, a rubber polymer containing at least one
kind selected from polyisobutylene, polyisoprene and styrene-dienestyrene
block copolymer (styrene-butadiene-styrene block copolymer (SBS),
styrene-isoprene-styrene block copolymer (SIS) etc.) as a main component
is preferable. Since drug stability is high, and the necessary adhesive
force and cohesion strength can be simultaneously achieved, a mixture of
a rubber polymer containing a high molecular weight polyisobutylene with
a viscosity average molecular weight of 500,000-2,100,000, and a low
molecular weight polyisobutylene with a viscosity average molecular
weight of 10,000-200,000 at a weight ratio of 95:5-5:95 is particularly
preferable.

[0052] When a rubber polymer is used, a tackifier is further preferably
added to impart adhesiveness at ambient temperature to an adhesive layer.
As a tackifier, those known in the relevant technical field can be
appropriately selected for use. Examples of the tackifier include
petroleum resin (e.g., aromatic petroleum resin, aliphatic petroleum
resin), terpene resin, rosin resin, coumarone indene resin, styrene resin
(e.g., styrene resin, poly(α-methylstyrene) etc.), hydrogenated
petroleum resin (e.g., alicyclic saturated hydrocarbon resin etc.) and
the like. Among these, an alicyclic saturated hydrocarbon resin is
preferable since it improves stability of the drug. Tackifier may be a
combination of one or more kinds thereof. The amount of the tackifier is
generally 33-300 wt %, preferably 50-200 wt %, relative to the total
weight of the rubber polymer.

[0053] When desired, for example, for adjustment of adhesiveness,
acceleration of transdermal absorption of a drug and the like, the
adhesive layer may contain an organic liquid component. The organic
liquid component is an organic compound which is liquid at room
temperature (25° C.) and plasticizes an adhesive layer. Examples
thereof include glycols such as ethylene glycol, diethylene glycol,
triethylene glycol, propylene glycol, polyethylene glycol, polypropylene
glycol and the like; fats and oils such as olive oil, castor oil,
squalene, lanolin and the like; organic solvent such as ethyl acetate,
ethyl alcohol, dimethyldecyl sulfoxide, methyloctyl sulfoxide, dimethyl
sulfoxide, dimethylformamide, dimethylacetamide, dodecylpyrrolidone,
isosorbitol and the like; liquid surfactant; plasticizers such as
octyldodecanol, diisopropyladipate, phthalic acid ester, diethylsebacate,
triethyl citrate, acetylcitric acid tributyl and the like; hydrocarbons
such as liquid paraffin and the like; ethoxylated stearyl alcohol; fatty
acid ester; glycerol acid ester and the like.

[0055] To maintain compatibility with the polymer in an adhesive layer and
prevent volatilization in the heating step during preparation of a patch
preparation, a fatty acid ester comprised of a higher fatty acid having a
carbon number of 12-16, (more preferably 12-14) and a lower monovalent
alcohol having a carbon number of preferably 1-4 is preferably used.
Examples of the higher fatty acid having a carbon number of 12-16 include
lauric acid, myristic acid, palmitic acid and the like, and examples of
the lower monovalent alcohol having a carbon number of 1-4 include methyl
alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol and the like.

[0056] As the glycerol acid ester (mono, di, or triglyceride), glycerol
middle chain (carbon number 8-12) fatty acid ester is preferable, and may
be any one of monoglyceride, diglyceride and triglyceride, or a mixture
of two or more kinds thereof, with preference given to triglyceride. As
the medium-chain triglyceride, a triglyceride wherein only one kind of
middle chain fatty acid is ester bonded to glycerol (e.g., caprylic acid
triglyceride wherein only caprylic acid is ester bonded to glycerol,
capric acid triglyceride wherein only capric acid is ester bonded and the
like) may be used, or a triglyceride wherein multiple kinds of middle
chain fatty acid are ester bonded to glycerol (e.g., (caprylic
acid-capric acid)triglyceride wherein caprylic acid and capric acid are
ester bonded to glycerol, (caprylic acid-capric acid-lauric
acid)triglyceride wherein caprylic acid, capric acid and lauric acid are
ester bonded to glycerol, and the like) may be used.

[0057] When desired, the adhesive layer may be applied to physical
crosslinking by irradiation such as ultraviolet irradiation, electron
beam irradiation and the like, or chemical crosslinking treatment using
an isocyanate compound such as trifunctional isocyanate and the like and
various crosslinking agents such as organic peroxide, organic metal salt,
metal alcoholate, metal chelate compound, multifunctional compound
(multifunctional external crosslinking agent, or multifunctional internal
crosslinkable monomer such as diacrylate, dimethacrylate and the like)
and the like to give a crosslinked adhesive layer. The crosslinked
adhesive layer containing an organic liquid component is preferable since
it has appropriate skin adhesiveness due to its gel state, and cohesive
property that does not leave an adhesive residue on detachment.

[0058] To protect an adhesive face of the adhesive layer before use, a
release liner may be applied. While the release liner is not particularly
limited, plastic films such as a polyester film, specifically a
polyethylene terephthalate film and the like, and a laminate film thereof
can be mentioned. Since the number of kinds is many, has an appropriate
thickness as a patch preparation, and materials are easy to select, a
polyester film, particularly a polyethylene terephthalate film is
preferable.

[0059] In consideration of easy processing and processing precision, a
release liner having a uniform thickness is preferable. While the
thickness is not particularly limited, from the aspects of easy
production of a patch preparation, cost of release liner, portability of
patch preparation, operability and the like, it is preferably 25
μm-200 μm, more preferably 50 μm-150 μm. To further
facilitate detachment of the release liner from the adhesive layer, a
surface release treatment (surface treatment with silicone release agent,
fluorine release agent, wax and the like) may be applied to the surface
on the adhesive layer side of the release liner.

[0060] When desired, the patch preparation of the present invention can be
packed in a packaging container known per se. As the packaging container,
one made of a resin film, a metal foil or a laminate film thereof is
generally used.

[0061] While a method of producing the patch preparation of the present
invention, namely, a patch preparation wherein a crystal of a drug is not
formed in the adhesive layer immediately after application of a physical
stimulation to the adhesive layer, but formed during preservation after
the physical stimulation, is not particularly limited, the following
method is preferable.

[0062] A release liner is prepared, an adhesive layer is laminated on one
surface of the release liner, and a support is laminated on the adhesive
layer to give a laminated sheet. Alternatively, a support is prepared, an
adhesive layer is laminated on one surface of the support, and a release
liner is laminated on the adhesive layer to give a laminated sheet. That
is, a laminated sheet wherein support/adhesive layer containing a
drug/release liner are laminated in this order is obtained. A method of
lamination is not particularly limited, and coating, adhesion,
heat-sealing, fusion splicing and the like can be mentioned. The method
of laminating an adhesive layer on a release liner or a support
preferably includes steps of preparing a composition for forming an
adhesive layer, which contains a drug, a polymer, an organic solvent and
the like, applying same on a release liner or a support, and removing the
organic solvent by drying.

[0063] A laminated sheet containing the obtained adhesive layer is cut
into the form of a patch preparation in a cutting step and, where
necessary, packed in a packing container to give a patch preparation
precursor. The patch preparation precursor here means a product which has
been processed from the laminated sheet into the form and size of a patch
preparation by cutting processing and, where necessary, packed in a
packing container, and prior to a heating step. In this case, the
obtained laminated sheet as a whole can be subjected to the cutting step
to cut the adhesive layer. The cutting step can be performed by cutting
with an edge tool such as a cutter, punching edge and the like.

[0064] The obtained patch preparation precursor is heated to give a patch
preparation. In the above-mentioned cutting step, an impact (physical
stimulation) is applied to the adhesive layer, which is assumed to cause
formation of a crystal core of the drug in the adhesive layer. By heating
the adhesive layer to a particular temperature, preferably not higher
than the melting point of the drug, the crystal core can be dissolved.
Preferable heating temperature and time are those sufficient to
completely dissolve all crystal cores of the drug in the adhesive layer.
When the crystal core is once completely dissolved in the adhesive layer,
crystal is not easily formed and the crystal formation can be stably
suppressed.

[0065] The patch preparation precursor is preferably heated immediately
after obtaining the patch preparation-precursor. When the patch
preparation precursor is left standing for a long time before heating,
crystal cores of the drug generated in the adhesive layer due to an
impact (physical stimulation) in the cutting step to give the patch
preparation precursor may grow too large while being left standing to be
completely dissolved in the heating step. While an acceptable time period
from obtaining a patch preparation precursor to heating thereof cannot be
determined easily since it depends on the drug concentration of the
adhesive layer, it is the period when the grown crystal cannot be
visually confirmed.

[0066] The heating temperature needs to be not less than 40° C. and
less than 100° C. and less than the melting point of the drug,
which is preferably not less than 40° C. and less than 91°
C. and less than the melting point of the drug, more preferably not less
than 54° C. and less than 84° C. and less than the melting
point of the drug. When the heating temperature is not less than the
melting point of the drug, the drug may be degraded, and the packing
container may be melted. On the other hand, when the heating temperature
is much lower than the melting point, a temperature for the saturating
concentration may not be reached, leaving the drug in crystals in the
adhesive layer. In addition, even if the heating temperature is less than
the melting point of the drug, when the heating temperature exceeds
100° C., inconveniences such as possible denaturation of an
adhesive component in the adhesive layer, melting of a packing container
when it is used and the like may occur.

[0067] While the heating time is not particularly limited as long as it is
sufficient to dissolve a drug in the adhesive layer, it is, for example,
3-120 hr, preferably 6-72 hr, more preferably 9-72 hr. When the heating
time is too long, a decrease in the drug content due to degradation of
the drug, and color change of the adhesive layer caused by impurities
resulting from degradation of the drug, such as oxide, decomposition
product and the like, are feared. On the other hand, when it is too
short, crystal cores cannot be dissolved, and crystal formation cannot be
prevented.

[0068] A cooling step may be added after a heating step. Since additional
facility and step are not required, cooling is preferably natural cooling
at environmental temperature.

[0069] The thus-produced patch preparation is stored until shipping.
During the storage, a patch preparation is generally left in an
environment of temperature 5-25° C., relative humidity 10-75% RH.
When the drug easily forms a hydrate, the patch preparation is preferably
stored under dry conditions (relative humidity: 10% RH±5% RH). To
avoid doubt, it is noted that "under dry conditions" refers to the
conditions of atmosphere to be in direct contact with the patch
preparation, and does not refer to the atmosphere with which the patch
preparation does not directly contact, for example, the atmosphere
outside the package body and when the patch preparation is housed in a
package body.

[0070] The drug that easily forms a hydrate is a drug having properties to
form a hydrate crystal at room temperature (25° C.), relative
humidity 0-98% RH. A number of drugs that easily form a hydrate are
already known, and specific examples thereof include scopolamine, citric
acid, theophylline and pharmaceutically acceptable salts thereof and the
like. Whether a drug easily forms a hydrate can be known by the following
test method.

[Test Method 1]

[0071] According to solid-water interaction: absorption and desorption
isothermal lines and measurement of water activity described in draft
revision (as of Dec. 10, 2010) scheduled for listing in Supplement 1 to
the Japanese Pharmacopoeia, 16th Edition, an adsorption isothermal line
and a desorption isothermal line of the drug are formed using a water
vapor automatic adsorption desorption apparatus. In the measurement,
relative humidity is increased from 0 to 98% RH under atmospheric
pressure at 25° C. at 5-10% distance, then decreased from 98 to 0%
RH at 5-10% distance in the same manner, and balancing weight is measured
in each atmosphere. With regard to the obtained adsorption isothermal
line and desorption isothermal line, the following are confirmed:

(i) in the adsorption isothermal line, the maximum change in the weight
of the drug before measurement is not less than 1.0 wt %, (ii) at least
in the adsorption isothermal line, an inflection point is observed, and
(iii) hysteresis is observed in the adsorption isothermal line and the
desorption isothermal line.

[0072] The "hysteresis is observed" means that the difference between the
inflection point of the adsorption isothermal line and that of the
desorption isothermal line is not less than 10%.

[Test Method 2]

[0073] TG curve of a drug is formed according to JIS K 7120-1987, and the
weight decrease rate is calculated. The weight decrease rate means change
in the weight of the drug at the completion of the measurement to the
weight of the drug before measurement, and whether the weight decrease
rate is not less than 1.0 wt % is confirmed.

[Test Method 3]

[0074] DSC curve of a drug is formed according to the Japanese
Pharmacopoeia, 15th Edition, General Test, 2.52 Thermal Analysis, Method
1. The temperature rise rate during the measurement is the same as in
Test method 2. Whether an endothermic peak (downward convex peak) is
observed in the DSC curve at the temperature of the inflection point in
the TG curve formed in Test method 2 is confirmed.

[0075] A drug that satisfies all of (i)-(iii) in the above-mentioned Test
method 1, Test method 2 and Test method 3 is judged as a drug that easily
forms a hydrate.

[0076] A drug that does not easily form a hydrate in the context of the
present specification refers to drugs other than the above-mentioned drug
that easily forms a hydrate. Specific examples of the drug that does not
easily form a hydrate include miconazole, isosorbide dinitrate,
ibuprofen, diclofenac, edaravone, tulobuterol, donepezil and
pharmaceutically acceptable salts thereof.

[0077] When a drug does not easily form a hydrate is used, crystal
formation of the drug can be suppressed even without storage of a
preparation under a dry atmosphere. Therefore, the present invention can
be practiced more advantageously. That is, using a drug that does not
easily form a hydrate, crystal formation of the drug dissolved in an
adhesive layer during the heating step of a patch preparation precursor
can be suppressed irrespective of storage of the patch preparation after
production under high humidity conditions or low humidity conditions. On
the other hand, when a drug that easily forms a hydrate is used, the drug
in an adhesive layer may form a hydrate when the patch preparation after
production is stored under high humidity conditions. In this case, even
when crystals of the drug are dissolved in the heating step of a patch
preparation precursor, a hydrate crystal of the drug may be formed.

[0078] The present invention is explained in more detail in the following
by referring to Examples. The present invention is not limited by the
following Examples, and various modifications may be made without
departing from the spirit of the present invention before practicing the
invention, which are all encompassed in the technical scope of the
present invention. In the following description, unless otherwise
specified, "parts" and "%" mean "parts by weight" and "wt %",
respectively.

[0081] Starting materials were mixed in the amounts shown in Tables 1 and
2 to give compositions for forming an adhesive layer, which were applied
to one surface of a polyethylene terephthalate film (hereinafter to be
indicated as PET, thickness 75 μm) as a release liner such that the
thickness after drying was 200 μm, and dried to form an adhesive
layer. To the adhesive layer was adhered a non-woven fabric surface of a
PET film (thickness 2 μm)-PET non-woven fabric (fabric weight 12
g/m2) laminate as a support, and the resulting product was subjected
to an aging treatment (crosslinking treatment of the adhesive layer) at
70° C. for 48 hr to give a laminated sheet. The laminated sheet
after the aging treatment was cut into a shape of a patch preparation,
and packed in a packing container under an atmosphere of oxygen
concentration not more than 3% to give a patch preparation precursor. In
Examples 7-19 and Comparative Examples 5-7, a PET film (thickness 25
μm) was used as a support, the thickness of the adhesive layer after
drying was 100 μm, and the aging treatment (crosslinking treatment of
the adhesive layer) was omitted. These changes do not influence the
presence or absence of the crystal formation of the drug.

[0082] The obtained patch preparation precursors were heated at the
temperature and time of the heating conditions shown in Tables 1 and 2,
and cooled by itself to the environmental temperature to give the patch
preparations of Examples 1-19, Comparative Examples 1-7 and Reference
Examples 1 and 2. The melting point of each drug and whether or not a
crystallization peak (indicated as Tc in the Tables) was detected by DSC
are shown in Tables 1 and 2.

3. Reference Example 3

[0083] In the same manner as in Example 3 except that, in Example 3, the
cutting step was omitted by forming an adhesive layer by casting a
composition for forming an adhesive layer into a container with a shape
of a patch preparation and after a release treatment of the inside, such
that the thickness of the adhesive layer after drying was 200 μm, and
drying same, and the heating step was omitted, the patch preparation of
Reference Example 3 was obtained.

[0091] The patch preparation packed in a packing container immediately
after production was stored in an incubator at 5° C. or 25°
C. for 6 months. During the storage period for 6 months, the patch
preparation was taken out from the incubator, and observed for crystal
formation of the drug on the adhesive face of the adhesive layer and the
inside thereof by visual observation and optical microscopic observation
(magnification: 100-fold). A patch preparation that did not show crystal
formation of the drug on the adhesive face of the adhesive layer and the
inside thereof by visual and optical microscopic observation
(magnification 100-fold) was evaluated as ◯, a patch
preparation that did not show crystal formation of the drug on the
adhesive face of the adhesive layer and the inside thereof by visual
observation but showed slight crystal formation by optical microscopic
observation (magnification: 100-fold) was evaluated as Δ, and a
patch preparation that showed clear crystal formation by visual
observation was evaluated as x.

5. Evaluation of Drug Stability

[0092] In the patch preparations of Examples 1-6, Comparative Examples
1-3, and Reference Examples 1-2, the drugs in the patch preparations
immediately after production were extracted with methanol, and analyzed
by high performance liquid chromatography (hereinafter to be referred to
as HPLC) to evaluate the impurity rate (in HPLC chart, the ratio of
summation of peak area corresponding to drug impurity to peak area
corresponding to drug) of the drug. A patch preparation that showed an
impurity rate of not less than 0.5% was evaluated as x, and a patch
preparation that showed an impurity rate of less than 0.5% was evaluated
as ◯.

6. Evaluation of Drug Release Property

[0093] With regard to the patch preparations of Examples 1-6, Comparative
Examples 1-3, and Reference Examples 1-2, the drug release property of
the patch preparations packed in packing containers was evaluated after
storage of the patch preparations at 25° C. for 6 months. The
release test of the patch preparations was performed according to U.S.
Pharmacopeia 26, <724> Drug Release, Transdermal Delivery
Systems-General Drug Release Standards, and a release solution was taken
after 0.25, 0.5, 4 and 24 hr from the start of the test. The recovered
release solution was filtered with a membrane filter, quantified by HPLC,
and measured for the amount of the released drug. The drug release rate
was calculated as the percentage of the amount of the drug (weight)
released after a given time relative to the amount of the drug (weight)
contained in the patch preparation before the drug release.

[0094] The drug release rate after a given time of the patch preparation
stored at 25° C. for 6 months and that of the patch preparation
immediately after production were compared, and a patch preparation
without change was evaluated as 0, and a patch preparation with change
was evaluated as x. Here, "without change" means that the difference
between a patch preparation stored at 25° C. for 6 months and a
patch preparation immediately after production was within 3% in all drug
release rates that were taken after 0.25-4 hr from the start of the test.

7. Color Change

[0095] With regard to the patch preparations of Examples 1-6, Comparative
Examples 1-3, and Reference Examples 1-2, the color value of a patch
preparation immediately after production was measured in the
CIE1976(L*a*b*) color system with a color difference meter (manufactured
by Konica Minolta Holdings, Inc., model number CR-400) and according to
the attached manual.

[0097] In the formula, (L*1,a*1,b*1) is a color value of the standard
color, and (L*2,a*2,b*2) is a color value of the evaluation subject. A
patch preparation with a ΔE value of less than 2 was evaluated as
◯, and a patch preparation with a ΔE value of 2 or more
was evaluated as x.

E={(L*2-L*1)2+(a*2-a*1)2+(b*2-b*1)2}1/2 (I)

8. Measurement of Saturating Concentration in Adhesive Layer

[0098] Patch preparations having an incrementing drug weight concentration
by 1 wt % were prepared, and a liner on the adhesive layer of each patch
preparation was detached. After standing the drug on the surface of the
adhesive layer, the liner was laminated again on the adhesive layer and
the resulting product was stored in an incubator at 25° C. for 6
months. The patch preparation was taken out from the incubator every one
month during the preservation for 6 months, and size change of the
standing drug was visually and optical microscopically observed
(magnification 500-fold). The maximum concentration with no change of the
drug size was judged as the saturating concentration in the adhesive
layer of the drug.

[0099] When the saturating concentration was evaluated as less than 1%
(the size of the standing drug grows even in a patch preparation having a
drug concentration of 1 wt %), patch preparations having an incrementing
drug concentration by 0.2 wt % were prepared within the drug
concentration range of 0-1 wt %, and a saturating concentration was
measured again in the same manner as above.

9. Crystal Formation of Drug in Adhesive Layer Due to Physical Stimulation

[0100] An adhesive layer of the patch preparation was pierced through with
a cutter to give a physical stimulation. These were packed in packing
containers and preserved at 25° C. and 60% RH for 6 months. To
determine whether a crystal of the drug was formed in the adhesive layer
before physical stimulation, immediately after application of physical
stimulation (not less than 0 hr and within 24 hr after physical
stimulation), and after physical stimulation (not less than 24 hr and
within 6 months after physical stimulation), the adhesive face of the
adhesive layer and the inside thereof were observed visually and with an
optical microscope. A patch preparation with crystal formation by visual
observation and optical microscopic observation (magnification 500-fold)
was evaluated as Y, a patch preparation without crystal formation by
visual observation and optical microscopic observation (magnification
500-fold) was evaluated as N, and a patch preparation without crystal
formation by visual observation but with crystal formation by optical
microscopic observation (500-fold) was evaluated as S.

[0102] From the test results, the following consideration was obtained.

[0103] By comparison of Comparative Example 3 and Example 3 produced via
the patch preparation precursors produced in the same formulation, in
Comparative Example 3 obtained by heating the patch preparation precursor
at 60° C. for 3 hr, crystals were formed, while in Example 3
obtained by heating the patch preparation precursor at 60° C. for
12 hr, a crystal was not formed. In addition, Reference Example 1
produced by heating the same patch preparation precursor as those of
Comparative Example 3 and Example 3 at 60° C. for 200 hr did not
form a crystal. However, the drug stability was low, and color change was
marked. Therefore, when the heating time of the patch preparation
precursor is too short, the crystal core formed in the production step
cannot be dissolved completely, and crystal formation during storage of
the preparation after production cannot be completely prevented.
Moreover, when the heating time of the patch preparation precursor is too
long, the drug was degraded, and drug stability and appearance were
impaired, though crystal was not formed during storage of the preparation
after production.

[0104] In addition, in Comparative Example 2 obtained by heating the patch
preparation precursor at 30° C. for 200 hr, crystals were formed
during storage of the patch preparation after production. Furthermore, in
Reference Example 2 obtained by heating the patch preparation precursor
at 100° C. for 3 hr, a crystal was not formed during storage of
the patch preparation after production. However, the drug was degraded,
and drug stability and appearance were impaired. Therefore, it has been
clarified that a low heating temperature of the patch preparation
precursor results in a failure to completely dissolve crystals of the
drug generated in the production step, and a high heating temperature of
the patch preparation precursor leads to degradation of the drug in the
patch preparation.

[0105] In Example 11, a crystal was not formed immediately after
application of a physical stimulation to the adhesive layer. However, a
crystal of the drug was formed during preservation after the physical
stimulation. On the other hand, in Comparative Example 5, a crystal was
not formed during preservation after application of physical stimulation.
In Comparative Example 5, sufficient skin permeability of the drug could
not be achieved, since the drug concentration in the patch was lower than
that in Example 11.

[0106] In Comparative Example 6, a crystal of the drug was formed in the
adhesive layer within 24 hr after application of a physical stimulation.
Therefore, Comparative Example 6 permits easy crystal formation of the
drug, and it is expected that crystals will cover the surface of the
adhesive layer before actually applying the patch preparation to the skin
of patients. As a result, the adhesion area will be decreased, and the
adhesiveness to the skin will also be decreased.

[0107] Furthermore, in Comparative Example 7, crystals were already formed
even before application of a physical stimulation and the adhesiveness to
the skin decreased as in Comparative Example 6, which prevents easy use
of the patch preparation.

[0108] In Example 18, a crystal of the drug was slightly observed before
application of a physical stimulation, and within 24 hr after the
physical stimulation. However, the amount of crystal was sufficiently
small and did not influence adhesiveness to the skin during use. That the
crystal was slightly observed means absence of crystal by visual
observation, but found under an optical microscope (500-fold). In
addition, since crystals were observed 24 hr after and within 6 months of
the physical stimulation by visual observation, sufficient skin
permeability of the drug was afforded.

[0109] From the results of Example 11-Example 19, it is appreciated that
in a patch preparation in which a ratio of the weight concentration to
the saturating concentration is 100-300%, crystals do not form
immediately after application of a physical stimulation to the adhesive
layer, but crystals are precipitated within 6 months, irrespective of the
polymer, liquid component and drug contained in the patch preparation.

[0110] In Example 3, a crystal of the drug was formed in the adhesive
layer due to application of a physical stimulation to the adhesive layer.
However, in Comparative Example 4, a crystal was not formed. In Reference
Example 3 without cutting processing of the adhesive layer, a crystal of
the drug was not formed before physical stimulation. However,
preservation after physical stimulation to the adhesive layer resulted in
the crystal formation of the drug. In Example 3 and Reference Example 3,
crystal formation of the drug in the adhesive layer was not observed at
24 hr after the start of the preservation. These results indicate that
drug concentration and skin permeability of the drug are low in
Comparative Example 4 that did not show crystal precipitation even with
physical stimulation, and skin permeability of the drug is sufficient in
Example 3 that showed crystal precipitation due to physical stimulation.

[0111] To investigate the influence of humidity during storage of the
patch preparation after production on crystal formation, the patch
preparation of Example 12 was subjected to a further storage test at high
humidity and low humidity. The high humidity storage test was performed
by storing a patch preparation immediately after production, in an
incubator at 25° C. (high humidity (humidity: 75% RH)) for 1 month
without packing in a packing container, crystal formation was observed
and evaluated in the same manner as in the above-mentioned "4.
Observation of crystal formation". The low humidity storage test was
performed by storing a patch preparation immediately after production, in
an incubator at 25° C. (low humidity (humidity: 10% RH)) for 1
month without packing in a packing container, crystal formation was
observed and evaluated in the same manner as in the above-mentioned "4.
Observation of crystal formation". Thereafter, the adhesive layer was cut
through with a cutter to apply physical stimulation, and the adhesive
layer was preserved under the same conditions as before the physical
stimulation. The adhesive face of the adhesive layer and the inside
thereof were observed with an optical microscope (magnification 500-fold)
before physical stimulation, immediately after physical stimulation (not
less than 0 hr and within 24 hr after physical stimulation), and after
physical stimulation (not less than 24 hr and within 6 months after
physical stimulation). A patch preparation with crystal formation was
evaluated as Y, and a patch preparation without crystal formation was
evaluated as N. The results are shown in Table 4. Isosorbide dinitrate is
a drug that does not form a hydrate with ease.

[0112] From Table 4, it is clear that the patch preparation containing
isosorbide dinitrate, in which a hydrate crystal was not formed with ease
(Example 12), affords sufficient skin permeability even when the patch
preparation after production is stored in high humidity.

[0113] This application is based on patent application Nos. 2010-077320
and 2011-61515 filed in Japan, the contents of which are incorporated in
full herein.

Patent applications by Akinori Hanatani, Osaka JP

Patent applications by Arimichi Okazaki, Osaka JP

Patent applications by Hitoshi Akemi, Osaka JP

Patent applications by Kensuke Matsuoka, Osaka JP

Patent applications by Sachiko Sakamoto, Osaka JP

Patent applications by Yoshihiro Iwao, Osaka JP

Patent applications by NITTO DENKO CORPORATION

Patent applications in class PREPARATIONS CHARACTERIZED BY SPECIAL PHYSICAL FORM

Patent applications in all subclasses PREPARATIONS CHARACTERIZED BY SPECIAL PHYSICAL FORM